Inappropriate gold standard bias in cervical cancer screening studies

As acetic acid-aided visual inspection (VIA) and colposcopic-directed biopsy miss small >/=cervical intraepithelial neoplasia (CIN) 2, inflation of sensitivity of VIA may occur when colposcopic-directed biopsy is the gold standard for >/=CIN 2. To determine whether such inflation occurs, we reviewed 375 women with >/=CIN 2 from the Shanxi Province Cervical Cancer Screening Study II. These women had positive self or physician-collected tests for high-risk human papillomavirus or abnormal cervical cytology and had VIA followed by colposcopy with directed biopsy and endocervical curettage (ECC). If a cervical quadrant had no lesion, a random biopsy at the squamocolumnar junction within that quadrant was obtained. Sensitivity of colposcopic-directed biopsy was higher for >/=CIN 2 involving 3-4 cervical quadrants (81.3%) than for >/=CIN 2 involving 0-2 quadrants (49.0%, p < 0.001). Sensitivities of VIA, cytology of >/=ASC-US, >/=LSIL, and >/=HSIL were higher for >/=CIN 2 involving 3-4 quadrants than for >/=CIN 2 involving 0-2 quadrants. When a colposcopic-directed biopsy gold standard was compared with that of a 5-biopsy standard (which included >/=CIN 2 from colposcopic-directed biopsy, random biopsy, or ECC), the sensitivity for >/=CIN 2 of VIA was inflated by 20.0% (65.9% vs. 45.9%, p < 0.001). Sensitivities of other screening tests were not affected. Similar inflation of sensitivity of VIA was found with an endpoint of >/=CIN 3 (70.4% vs. 52.0%, p = 0.0013). Inflation of sensitivity of VIA depended upon agreement between colposcopic-directed biopsy and the screening tests as measured by kappa. Studies of VIA that used colposcopic-directed biopsy as the gold standard require reevaluation.